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Designing HER2 vaccines
Teresa M Foy1, Gary R Fanger, Susan Hand
1Corixa Corporation, Seattle, WA 98104, USA.
Abstract:
HER2/neu is a compelling cancer vaccine candidate because it is overexpressed on some cancer cells relative to normal tissues, it is known to be immunogenic in both animal models and in humans, and it is already known to be targetable by the antibody component of the immune system in the form of monoclonal antibody therapy with trastuzumab. Vaccines offer the theoretical advantage of being able to elicit T-cell responses in addition to antibody responses. HER2 vaccines have been shown to provide benefit in animal models and to be immunogenic in humans. However, the optimal vaccine formulation is not yet known and the therapeutic efficacy of the vaccines in humans has not yet been evaluated. HER2 vaccine approaches currently being tested include peptide-based, DNA plasmid-based, and protein-based vaccines. Our group has developed and started testing a protein-based vaccine composed of both the extracellular domain of HER2 and the carboxyl terminal autophosphorylation portion of the intracellular domain. The extracellular domain was retained to provide for antibody targeting. The kinase domain of the intracellular domain was excluded because of its high degree of homology to other human kinases. The carboxyl terminal autophosphorylation domain was retained because it is the most unique and possibly most immunogenic portion of the HER2 molecule with the least homology to other members of the HER family. The vaccine, termed dHER2, is immunogenic in mice and primates. In animal models it can elicit CD8 and CD4 T-cell responses as well as antibody responses that suppress the growth of HER2-positive cancer cells in vitro and in vivo. Vaccine trials are contemplated in patients with breast cancer that will determine whether the vaccine construct is similarly immunogenic in humans.
Insights
A novel HER2 cancer vaccine (dHER2) demonstrated immunogenicity in preclinical models, eliciting T-cell and antibody responses that suppressed tumor growth. Human trials are planned to evaluate its efficacy in breast cancer patients.
Area of Science:
- Oncology
- Immunology
- Vaccine Development
Background:
- HER2/neu is an attractive cancer vaccine target due to its overexpression on cancer cells and immunogenicity.
- Monoclonal antibody therapy (trastuzumab) targeting HER2 is established, but vaccines may elicit broader T-cell responses.
- Previous HER2 vaccine approaches have shown promise in animal models and immunogenicity in humans, but optimal formulations and human efficacy are undetermined.
Purpose of the Study:
- To develop and test a novel protein-based HER2 cancer vaccine (dHER2).
- To evaluate the immunogenicity and anti-tumor effects of the dHER2 vaccine in preclinical models.
- To establish the foundation for future human clinical trials in breast cancer patients.
Main Methods:
- Developed a protein-based vaccine (dHER2) comprising the extracellular domain and carboxyl-terminal autophosphorylation domain of HER2/neu.
- Excluded the kinase domain due to homology with other human kinases, retaining unique and potentially immunogenic regions.
- Assessed vaccine immunogenicity and anti-tumor activity in mouse and primate models, measuring T-cell (CD8, CD4) and antibody responses.
Main Results:
- The dHER2 vaccine was immunogenic in mice and primates.
- It elicited robust CD8 and CD4 T-cell responses, as well as antibody responses.
- In animal models, dHER2 vaccination suppressed the growth of HER2-positive cancer cells both in vitro and in vivo.
Conclusions:
- The dHER2 vaccine is a promising candidate for HER2-targeted cancer immunotherapy.
- Preclinical data support its ability to induce both cellular and humoral immune responses.
- Further investigation in human clinical trials is warranted to assess therapeutic efficacy in patients with HER2-positive cancers, particularly breast cancer.